Dichloro trifluoromethyl benzoic acids and their preparation

ABSTRACT

DICHLORO TRIFLUOROMETHYL BENZOIC ACIDS ARE PREPARED BY REACTING A DICHLORO TRIFUOROTOLUENE WITH AN ALKYL LITHIUM COMPOUND AND TREATING THE RESULTING COMPOUNDS WITH CARBON DIOXIDE. THE RESULTING BENZOIC ACIDS ARE USEFUL AS CNS DEPRESSANTS AND AGROCHEMICAL AGENTS.

United States Patent Office 3,592,842 Patented July 13, 1971 U.S. Cl.260-515 6 Claims ABSTRACT OF THE DISCLOSURE Dichloro trifiuoromethylbenzoic acids are prepared by reacting a dichloro trifluorotoluene withan alkyl lithium compound and treating the resulting compounds withcarbon dioxide. The resulting benzoic acids are useful as CNSdepressants and agrochemical agents.

COOH

1 provided that Cl is restricted to either the A or B position, and whenCl is at A, COOH is at B.

More specifically, the preferred compounds of this invention are2,6-dichloro-3-trifluoromethyl benzoic acid,

COOH

2,3-dich1oro-S-trifluoromethyl benzoic acid,

COOH- Cl 2,3-dichloro-6-trifiuoromethyl benzoic acid COOH and3,4-dichloro-6-trifluoromethyl benzoic acid CO OH- The process forpreparing the compounds of Formula I may be represented by the followingreaction scheme:

OF CF C02 A Li C1 COOH Cl inert solvent B where Cl is restricted toeither the A or B position; and when Cl is at A, Li and COOH are at B.

Compounds I are prepared by treating in an inert solvent a correspondinglithium intermediate compound of Formula II with carbon dioxide. Thereaction may be conveniently carried out at a temperature of from 50 C.to 35 C. and preferably at a temperature of l0 C. to 10 C. The carbondioxide used can be a solid or gas. The solvent may be lowerhydrocarbons such as pentane, hexane, heptane and the like, ethers suchas diethyl ether, dibutyl ether and the like, tetrahydrofuran andbenzene.

The process for preparing compound (II) may be represented by thefollowing reaction scheme:

When Cl and Li have the above-stated restrictions, and R is a straightchain lower alkyl having 1 to 6 carbon atoms.

The intermediate lithium compound (II) may be prepared by reacting adichloro-trifiuorotoluene with a straight chain lower alkyl lithiumcompound (IV) having 1 to 6 carbon atoms in a solvent in the presence ofan inert gas. The preferred alkyl lithium compound is butyl lithium. Thesolvent may be lower hydrocarbons such as pentane, hexane, heptane, andthe like, ethers such as diethyl ether, dibutyl ether, and the like,tetrahydrofuran and benzene. The inert gas may be nitrogen, helium,argon, and the like. The reaction conveniently takes place attemperatures of 60 C. to 30 C. with the preferred temperature rangebeing 50 C. to 40 C.

When the starting material of Formula III is2,4-dichloro-a,a,a-trifluorotoluene,

the lithium intermediate has the structural formula I or I) When thestarting material of Formula 111 is 3,4-dichlorothe lithium intermediatecan be represented by the structural formula Using the reactiondescribed above for compound (1), compounds (Ia), (Ib), (Ic) and (Id)can be prepared. When 2,4-dichloro-ot,a,a-trifiuorotoluene (V) is thestarting material, the 2,6-diehloro-3-trifiuoromethyl benzoic acid (Ia)is obtained. Starting with 3,4-dichloro-a,a,a-trifluorotoluene (VII) amixture of the 2,3-dichloro-5-trifluoromethyl benzoic acid (Ib),2,3-dichloro-6-trifluoromethyl benzoic acid (Ic) and3,4-dichloro-6-trifluoromethyl benzoic acid (Id) is obtained with the2,3-dichloro-5-trifluoromethyl benzoic acid (Ib) predominating.Conventional recovery techniques are utilized for obtaining the products(Ia), (1b), (Ic) and (Id).

These acids may be converted to and from the basic addition salts usingconventional techniques, such as suspending or dissolving the acid inwater and treating the resulting material with a base, such as sodiumhydroxide.

The compounds of Formula III are known and are prepared by methodsdisclosed in the literature.

The bis(trifluoromethyDbenzoic acids represented by Formula I above, andtheir non-toxic basic addition salts, are useful because they possesspharmacological properties in animals, such as mammals. In particular,these compounds are useful as CNS depressants as indicated by theiractivity in mice given a 200 mg./kg. of active agent and testedaccording to the -word adjective check sheet system basically describedby Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) andChen (Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins,1954).

These bis(trifluoromethyl)benzoic acids or their salts may be combinedwith a pharmaceutically acceptable carrier or adjuvant. They may beadministered orally or parenterally. For this use, the dosage will varydepending upon the mode of administration utilized and the particularcompound employed. However, in general, satisfactory results areobtained when the compounds are administered at a daily dosage of fromabout 5 milligrams to 200 milligrams per kilogram of animal body weight.This daily dosage is preferably given in divided doses, e.g., 2 to 4times a day, or in sustained release form. For most large mammals, thetotal daily dosage is from about 250 to 750 milligrams, and dosage formssuitable for internal administration comprise from about 60 milligramsto about 375 milligrams of the compound in admixture with a solid orliquid pharmaceutical carrier or diluent.

(VII) (VIII) A representative formulation suitable for oraladministration is a tablet prepared by standard tabletting techniqueswhich contains the following:

Ingredient: Parts by Weight 2,6-dichloro-3-trifiuoromethyl benzoic acid25 Tragacanth 2 Lactose 64.5 Corn starch 5 Talcum 3 Magnesium stearate0.5

The compounds of this invention are also useful as agrochemical agents,particularly as herbicides and may be used for the destruction orprevention of weeds or unwanted plants.

They may be used as such on their own or preferably in combination withan agriculturally or herbicidally acceptable diluent or carrier.

The compounds of the Formula I in the form of free acids or asagriculturally or herbicidally acceptable basic addition salts may beworked up to give herbicidal compositions of which the exact nature mayvary greatly depending on the intended use. These compositions may beworked up in the usual way, if desired with the addition of adjuvants,to give preparations which may be used in the form of solutions,emulsions, suspensions, pastes, powders, strewing agents, dusting agentsand granulates, if desired after further dilution. Liquors forapplication in the control of plant growth should contain at least 0.02and preferably up to about 1% of an active agent of this invention. Itis also within the scope of the present invention to incorporate intothese herbicidal compositions adjuvants which facilitate distributionand increase the adhesion and stability to rain.

Depending on the purpose for which the preparation is to be used, it ispossible to add other materials having an influence on plant growth, forexample in order to widen the effect spectrum.

Herbicidal preparations containing a compound of this invention may beused in conventional manner, egg. (8.) by emulsification or suspensionof the preparation in water and spraying the plants to be treated, forexample by sprinkling or spraying a locus to be cultivated or protectedbefore the germination of any weeds, (b) by dusting already existingweeds, or (c) by direct application of a dusting or strewing agent orgranulate to the locus to be cultivated. If desired, the preparation mayalso be worked into the ground.

The compounds of Formula I may be applied at a dosage of 2-30 pounds peracre to produce a satisfactory herbicidal effect. An appropriatenon-selective dosage is 10-30 pounds per acre whereas a dosage suitablefor selective herbicidal action is 2-10 pounds per acre.

The invention is illustrated, but in no Way limited, by reference to thefollowing examples.

EXAMPLE 1 2,6-dichloro-3-trifiuoromethyl benzoic acid g. (0.79 mole) of2,4-dichloro 0c,oc,a trifiuorotoluene and 1000 ml. of absolutetetrahydrofuran were charged to a flask equipped with stirrer, droppingfunnel, carbon dioxide condenser and gas inlet tube. The system wasflushed with dry nitrogen and cooled (carbon dioxideacetone bath) to aninternal temperature of 50 C. A 660 ml. solution of 15% n-butyllithium(1.06 mole nbutyllithium) in hexane was added dropwise (20 minutes) tothe flask. The resulting dark red-purple solution was maintained at 50C. for about one hour, and then poured onto a slurry of 750 g. powderedcarbon dioxide and 250 ml. diethyl ether. After standing for about 20hours at room temperature, the residue was treated with 750 ml. of 2 Nsodium hydroxide. The caustic layer was washed with toluene, acidifiedwith concentrated HCl, extracted twice with 200 ml. of methylenechloride and dried with sodium sulfate. The methylene chloride layer wasfiltered and the solvent removed in vacuo. The residue was crystallizedfrom heptane to give 2,6-dichloro-3-trifiuoromethyl benzoic acid; M.P.90-92 C.

EXAMPLE 2 2,3-dichloro-5-trifluoromethyl benzoic acid2,3-dichloro-6-trifluoromethyl benzoic acid COOH3,4-dichloro-6-trifiuoromethyl benzoic acid CODE- toluene and 500 ml. ofabsolute tetrahydrofuran were charged to a flask equipped with stirrer,dropping funnel, carbon dioxide, condenser and gas inlet tube. The systerm was flushed with dry nitrogen and cooled (carbon dioxide-acetonebath) to an internal temperature of 50 C. A 220 ml. solution ofn-butyllithium (0.352 mole) in hexane was added dropwise minutes to theflask). The resulting dark red-purple solution was maintained at -50 C.for about one hour, and then poured onto a slurry of 350 g. powderedcarbon dioxide and 150 g. diethyl ether. After standing for about 20hours at room temperature the residue was treated with 300 ml. of 2 Nsodium hydroxide. The caustic layer was washed with toluene, acidifiedwith concentrated HCl, extracted twice with 200 ml. of methylenechloride and dried with sodium sulfate. The methylene chloride layer wasfiltered and the solvent removed in vacuo. The residue was crystallizedfrom heptane to give mainly a mixture of 2,3- dichloro-3-trifiuoromethylbenzoic acid, 2,3-dichloro-6- trifluoromethyl benzoic acid, and3,4-dichlor0-6-trifluoromethyl benzoic acid.

EXAMPLE 3 A test tube having a inch hole at the bottom is plugged at thehole with some glass woo-l. The test tube is then filled to about 1%inches from the top with quartz sand which is made inert by washing withacetone-distilled water (1: 1), distilled water, and dried. Seed of theplant to be tested is planted in the sand. The tube is fitted with arubber collar and suspended in an Erlenmeyer flask containingconventional KNOPS nutrient solution and the active agent of thisinvention at a concentration of 50 parts per million (no active agent incheck). The apparatus is placed under fluorescent lights for about threeweeks and once daily, the bottom of the tube is dipped into thesolution. The results are noted below when 2,6-

dichloro-3-trifluoromethy1 benzoic acid is used as active agent:

PERCENT OF CHECK Plant Root Test species seeds Height length CommentsField corn 2/4 6 17 Extreme epinasty, then N 0. 8. death; rootsextremely stunted and extremely discolored. Annual 2/4 8 9 Extremeepinasty and ryegrass. much necrosis, then death; roots extremely sparseand extremely stunted. Barnyard 4/4 9 29 Extreme epinasty, then grass.death; roots extremely sparse and extremely stunted. Wild oat 0/4 0 0 Nogermination. ohnson grass 0/4 0 0 D0. Wheat (Red 3/4 4 3 Extremeepinasty, then Coat). death; roots extremely sparse and extremelystunted. Soybean 0/4 0 0 No germination (Adelphia). CofieeweecL 0/4 0 0Do. Field bind- 0/4 0 17 N o germination; roots weed. extremely stuntedand extremely discolored. Redroot 6/8 15 7 Extreme epinasty, thenpigweed. death; roots extremely stunted. Cocklebur- 0/1 0 8 N ogermination; roots extremely stunted and extremely discolored. Cotton0/4 0 22 D0.

(Coker 201).

EXAMPLE 4 Using the procedure outlined in Example 3 and 2,3-dichloro-S-trifluoromethyl benzoic acid as the active agent, thefollowing results are obtained:

PERCENT OF CHECK Root Test species Seeds Height length Comments Fieldcorn 4/4 47 22 Chlorosis and much No. 8. epinasty, then death;

roots extremely stunted and extremely discolored. Annual rye 4/4 75 69Very slight necrosis.

grass. Barnyard 3/4 88 48 Very slight chlorosis;

grass. roots stunted. Wild oat 1/4 56 Very slight epinasty. Johnsongrass 3/4 67 Do. Wleatt)(Red 3/4 49 83 Minor epinasty.

0a Soybean 4/4 22 75 Extreme epinasty.

(Adelphia). Cofieeweed 4/4 60 100 Epinasty; roots sparse. Field bind-3/4 11 50 Much epinasty; roots weed. extremely stunted and extremelysparse. Redroot pig- 5/8 15 14 Chlorosis and epinasty,

weed. then death; roots extremely stunted. Cocklebur 1/1 39 21 Muchepinasty, then death; roots greatly stunted. Cotton 4/4 53 111 Epinasty,then death,

(Ooker 201) possibly due to fungal attack; roots extremely sparse.

EXAMPLE 5 Dust formulations The following compositions are adapted fordirect application as dusts for the destruction or prevention of weedsusing conventional dusting equipment. The dusts are made by blending ormixing the ingredients and grinding the mix to give compositions havingan average par ticle size less than about 50 microns.

Parts 2,6-dichloro-3-trifluoromethyl benzoic acid 20 Talc 100 Parts2,3-dichloro--trifluoromethyl benzoic acid 5 Cottonseed oil 4 Walnutshell flour 91 EXAMPLE 6 Water-dispersible liquid compositions Thefollowing compositions are in a liquid form and are adapted for additionto water to give aqueous dispersions for application as sprays. Theliquid or fiuid compositions shown are prepared by thoroughly mixing anddispersing active compounds and conditioning agent or agents in anorganic liquid diluent.

Parts 2,3-dichloro-6-trifluoromethyl benzoic acid 25 Long chain fattyalcohol sulfate (emulsifying agent) 2 What is claimed is: 1. A compoundof the formula COOH 0! 8 where Cl is in the A or B position, and then C1is at A, COOH is at B, or a basic addition salt thereof.

2. The compound of claim 1 which is 2,6-dichloro-3- trifluoromethylbenzoic acid.

3. The compound of claim 1 which is 2,3-dichloro-6- trifiuoromethylbenzoic acid.

4. The compound of claim 1 which is 2,3-dichloro-5- trifiuoromethylbenzoic acid.

5. The compound of claim 1 which is 3,4-dichloro-6- trifluoromethylbenzoic acid.

6. A process for the preparation of the compound of claim 1 whichcomprises treating in the presence of an inert gas and an inert solventat a temperature of 60 C. to 30 C. a compound of the formula where Cl isin the A or B position, with a compound of the formula RLi wherein R isstraight chain lower alkyl, to obtain a corresponding intermediatelithium compound and treating said intermediate at a temperature of C.to 35 C. in an inert solvent with carbon dioxide.

References Cited Hudlicky Chemistry of Organic Fluorine Compounds (1961)p. 224.

JAMES A. PA'I'IEN, Primary Examiner US. Cl. X.R.

